The utility of ctDNA in detecting minimal residual disease following curative surgery in colorectal cancer: a systematic review and meta-analysis

Abstract

Introduction: Colorectal cancer is the fourth most common cancer in the UK. There remains a need for improved risk stratification following curative resection. Circulating-tumour DNA (ctDNA) has gained particular interest as a cancer biomarker in recent years. We performed a systematic review to assess the utility of ctDNA in identifying minimal residual disease in colorectal cancer.

Methods: Studies were included if ctDNA was measured following curative surgery and long-term outcomes were assessed. Studies were excluded if the manuscript could not be obtained from the British Library or were not available in English.

Results: Thirty-seven studies met the inclusion criteria, involving 3002 patients. Hazard ratios (HRs) for progression-free survival (PFS) were available in 21 studies. A meta-analysis using a random effects model demonstrated poorer PFS associated with ctDNA detection at the first liquid biopsy post-surgery [HR: 6.92 CI: 4.49-10.64 p < 0.00001]. This effect was also seen in subgroup analysis by disease extent, adjuvant chemotherapy and assay type.

Discussion: Here we demonstrate that ctDNA detection post-surgery is associated with a greater propensity to disease relapse and is an independent indicator of poor prognosis. Prior to incorporation into clinical practice, consensus around timing of measurements and assay methodology are critical.

Protocol registration: The protocol for this review is registered on PROSPERO (CRD42021261569).

Fig. 1. PRISMA flow diagram.

Flow diagram describing the study selection process and number of studies at each stage according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines.

Fig. 2. Forest plot showing meta-analysis for PFS according to post-operative ctDNA following surgery for colorectal cancer.

Data displayed as HR with 95% confidence intervals on a logarithmic scale. HR hazard ratio, PFS progression-free survival, SE standard error.

Fig. 3. Subgroup analysis.

Forest plot showing subgroup meta-analysis for PFS according to post-operative ctDNA according to disease extent, adjuvant chemotherapy and assay type: a resection of primary disease; b metastasectomy, c did not receive adjuvant chemotherapy; d received adjuvant chemotherapy; e NGS; f PCR data displayed as HR with 95% confidence intervals on a logarithmic scale. HR hazard ratio, NGS next-generation sequencing, PCR polymerase chain reaction, PFS progression-free survival.

Fig. 4. Funnel plot.

Funnel plot to show effect size against standard error for HR of PFS according to ctDNA status. HR hazard ratio, PFS progression-free survival, SE standard error.